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Association between Vitamin D Receptor Gene Polymorphism and Sex-Dependent Growth during the First Two Years of Life¹

CNRS Unité de Recherche Associée 583 (F.S., F.Z., O.W., M.G.) - Université Paris V, Hôpital Saint Vincent de Paul, 75014 Paris, France; and Centre des Bilans de Santé de l’Enfant (C.R.), CPAM de Paris, 75011 Paris, France

Address all correspondence and requests for reprints to: M. Garabédian, CNRS URA 583, Hôpital Saint Vincent de Paul, 82 Avenue Denfert Rochereau, 75014 Paris, France.

	Abstract

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An association between vitamin D receptor (VDR) gene polymorphisms and bone mass variance has been observed in adult populations. To analyze possible association between VDR genotype and growth, we studied 589 healthy infants who were homogeneous for age, diet, and vitamin D status. The Bsm I, TaqI, and ApaI alleles’ frequencies and genotypes were similar to those reported for Caucasian populations. Variations in Bsm I polymorphism were not associated with calcium intakes nor with serum levels of calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, or alkaline phosphatase activity. But, they were associated with differences in body size. At 2 yr, homozygote BB (BsmI site absent) girls had higher length, weight and body surface area, and inversely, BB boys had lower weight, body mass index and body surface area, than their respective bb counterparts. As a result, gender-related differences were observed in Bb and bb, but not in BB populations. This VDR genotypic effect was observed also at birth and at 10 months in the longitudinal analysis of 145 selected full-term babies homozygous for the Bsm I polymorphism. These findings provide support for the hypothesis that VDR genotype influences intrauterine and early postnatal growth, directly or via interactions with gender-related growth regulators.

	Introduction

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THE RECENT demonstration by Morrison et al. of a vitamin D receptor (VDR) gene polymorphism with likely consequences on bone metabolism (1) has been a major breakthrough in the search for the genetic determinants of bone mass. Numerous studies since have analyzed restriction fragment length polymorphisms (RFLPs) of the VDR gene (1, 2, 3, 4, 5, 6, 7, 8, 9). So far, they have focused on the possible association between common allelic variation in the VDR locus and bone mass variance (3, 4, 5, 6, 7) or pathologies of calcium metabolism, like absorptive hypercalciuria (8) and hyperparathyroidism (9).

But physiological variations in the gene encoding the VDR may affect other vitamin D regulated events. We hypothesized that growth is one of those, based on several observations suggesting that vitamin D influences this multifactorial process. First, vitamin D metabolites regulate the proliferation, differentiation, and maturation of cells responsible for skeletal growth, namely, chondrocytes of the epiphyseal growth plate (10, 11) and osteoblasts (12). Second, severe vitamin D deficiency and hereditary defects in the production of 1,25-dihydroxyvitamin D are associated with growth failure (13). Third, children with a low vitamin D status at birth have delayed ponderal growth in their first year of life (14).

Growth velocity is at its highest level during infancy. This age is thus a period of particular interest for testing the hypothesis that VDR receptor genotype may be a determinant of the physiological variability in growth. To do so, we evaluated VDR genotype frequency in a unique cohort of 589 healthy infants homogeneous for age, diet, vitamin D status, and time of blood sampling. Cross-sectional data on body size in 423 unselected infants, longitudinal data on growth in 145 selected full-term babies homozygous for the Bsm I polymorphism, and serum concentrations of calcium, vitamin D metabolites, and alkaline phosphatase activity were analyzed to investigate their possible association with Bsm I polymorphism during the first 2 yr of life.

	Subjects and Methods

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The 589 infants recruited for the study were healthy infants seen at the Centre des Bilans de Santé de l’Enfant, CPAM (Paris, France) for a systematic physical and biological examination at either 10 months or 2 yr of age during the months of June and July. No information on geographical origin and past history and no blood samples other than those purposely collected for the checkup were used in this study. Two hundred forty-eight of the infants had all four grandparents of French Caucasian origin. The others were of mixed European origin or had one or more grandparents originating from North Africa (Maghreb).

An association between VDR gene polymorphism and anthropometric or biologic data could be investigated in 423 of these infants. Their mean age was 10.2 ± 0.6 months (mean ± 1 SD, n = 162) or 22.9 ± 1.2 months (n = 261). Age, crown-heel length, weight, body mass index (BMI, weight/height²), and body surface area were recorded for all children at the time of blood sampling. When available, longitudinal data on weight and length from birth to 2 yr of age and parents’ heights were recorded. Information on vitamin D intakes was collected for all children, as well as the intakes of milk products in the 10-month-old group. Breast-fed infants had been excluded from the study and all 10-month infants had received daily oral supplements of 1,000–1,500 IU vitamin D2 (mean intake: 1,143 IU/day), the usual French prophylaxis against vitamin D deficiency. The 2-yr-old infants had received either daily supplements of vitamin D or intermittent oral doses (2.5 mg every 3 months or 5 mg every 6 months).

Blood samples were those obtained from the capillary blood collected for the systematic checkup in the morning. Serum alkaline phosphatase activity, protein, and calcium concentrations were determined using an automatic autoanalyzer. To limit variations linked to protein-bound calcium, serum calcium was corrected for protidemia, according to the formula: corrected calcium = total calcium (mmol/L) - 0.0172 x protidemia (g/L) + 1.26. Serum vitamin D metabolites were assayed using inhouse competitive protein-binding assays (15, 16) with continuous external quality assessment of the 25-(OH)D assay (17).

Infants were genotyped for polymorphisms at the VDR gene by PCR. DNA was extracted from whole blood using a commercial kit. Two sequences were amplified containing the endonuclease Bsm I site (3) and the ApaI and TaqI sites (2). The RFLPs were coded as Bb (Bsm I), Aa (ApaI), and Tt (TaqI), where the uppercase letter signifies absence of the site and lowercase signifies presence of the site.

	Results

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As shown on Table 1, the Bsm I alleles’ frequencies in the 589 healthy infants living in the Paris area are roughly similar to those earlier reported for other Caucasian populations (7). BB alleles were found in 13–14% of the infants, while the bb alleles were found in 34–39%. The alleles’ frequencies in the subpopulation with four grandparents of French metropolitan origin were not different from those observed in the total cohort (Table 1). Bsm I, ApaI, and TaqI polymorphisms were analyzed in 158 of the infants, including 57 children with four grandparents originating from France. BB and tt alleles were in close linkage, and the genotype distribution was not different in the subpopulation with four French metropolitan grandparents, from that observed in the total cohort. Seven RFLP genotypes with a frequency higher than 1% were observed: BbAaTt (30%), bbAaTT (23%), bbaaTT (16%), BbAATt (13%), BBAAtt (9%), bbAATT (4%), and BbAaTT (2%), consistent with the relative distribution of VDR genotypes found in the Australian population (1).

View larger version (18K): [in this window] [in a new window]   Figure 1. Weight and length gain, in relation to VDR gene polymorphism. Weight and length have been measured at birth, 10 months, and 2 yr of age in 17 female (open symbols) and 13 male (closed symbols) full-term babies with the BB genotype (left part of the figure) and in 51 female (open symbols) and 64 male (closed symbols) full-term babies with the bb genotype (right part of the figure). Values are mean ±1 SD. *, P < 0.01; **, P < 0.005; and ***, P < 0.0005, as compared with girls of the same age and VDR genotype (unpaired Student’s t test).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Common allelic variations in the gene encoding the 1,25-dihydroxyvitamin D receptor represent one of the genetic determinants of bone mass and/or of bone mass variance with age, although the contribution of VDR polymorphism has not been found by all investigators and does not seem to be as important as proposed originally (1, 2, 3, 4, 5, 6, 7). Of interest, a recent meta-analysis of the published studies suggests a stronger association of the VDR polymorphism with bone mineral density in young adult women than during postmenopausal life (7).

Our results bring evidence that the VDR genotype also may be a determinant of growth during infancy. Previous works in infants or neonates have been published only as abstracts (18, 19). One did not show genotype-associated differences in length, weight, or changes in length and weight in the first year of life (18). But infants had not been separated according to their gender. The other found significant differences in mean weight at year one between female homozygotes for the TaqI polymorphism but not at birth and not in males (19). In the present cohort of healthy children homogeneous for age, diet, and vitamin D intakes, variations in VDR genotype were associated with marked differences in growth parameters when male and female populations were separated. At 2 yr of age, BB girls had higher length, weight, and body surface area, and inversely, boys with the BB genotype had lower weight, BMI, and body surface area than their respective bb counterparts. These variations are significant because mean differences in weight and length between infants with the BB and bb genotypes approximated 0.8–1 SD on reference growth curves for French children (20). Moreover, gender-related differences in weight, length, and body surface area were observed in the Bb and bb populations, as expected, but not in infants with the BB genotype. These observations suggest that variations in the VDR genotype may alter the effect of gender-related factors on growth during infancy.

In our cross-sectional study of unselected infant populations, an association between VDR genotype and body size was observed at 2 yr of age but not at 10 months. We hypothesized that possible interferences linked to the catch-up growth of premature babies may have masked the apparent VDR genotypic effect during the first year of life. We therefore selected a subgroup of infants who had been born after 37.5 weeks of pregnancy, were homozygous for the Bsm I polymorphism, and for whom data on body size had been recorded at 10 months and 2 yr of age in the same checkup center. The longitudinal analysis of growth patterns in full-term babies suggests that the apparent VDR genotypic effect observed in the unselected population of 2-yr-old infants manifests itself very early in life, because it is also observed at birth and at 10 months of age in full-term babies. This analysis also suggests a postnatal effect of the VDR genotype, as sex-related differences in weight gain were found in infants with the bb genotype during their first 2 yr of life but not in infants with the BB genotype. This suggests some linkage between VDR gene polymorphism and sex-dependent processes occurring before birth and possibly shortly after.

Findings of stronger associations between B allele and bone mass in subjects with low calcium intake (4, 5), and of some association of VDR genotype with fractional gut absorption (21), suggest a possible influence of VDR polymorphisms on the sensitivity of gut calcium absorption to 1,25-dihydroxyvitamin D. Such an effect cannot account for the present association between VDR genotype and early growth patterns because differences were already observed at birth. For the same reason, differences in dietary intakes of calcium cannot explain the present findings. In addition, calcium intakes (through milk products) at 10 months did not differ with the VDR genotype and corresponded to recommended dietary calcium allowances at this age (500 mg/day), an observation already reported in the same health center (22). Recruitment bias related to the vitamin D status of the infants is also unlikely, as evidenced by the similar serum 25-(OH)D levels in the different groups of children. Also, differences in linear growth could not be clearly attributed to differences in the parents’ height. Finally, the simultaneous analysis of growth, serum calcium levels, and vitamin D metabolite concentrations does not support the hypothesis that variations in vitamin D metabolism or calcium homeostasis mediate the observed association between VDR genotype and growth.

It thus remains possible that variations in the function or expression of the VDR, or of another gene in close linkage with the VDR polymorphism, directly influence cells responsible for skeletal and overall somatic growth, like osteoblasts, chondrocytes and fibroblasts, during fetal and early postnatal life. They also may modulate interactions, in these cells, between 1,25-dihydroxyvitamin D and sex-dependent regulating factors (like estradiol, for example). Indeed, these cells express VDR and respond to vitamin D (10, 11, 12), and additive or negative interactions between 1,25-dihydroxyvitamin D and estradiol have been reported in bone cells (23, 24). But 1,25-dihydroxyvitamin D and its receptor also may interact with other sex-related peptides or steroids, and the interaction site(s) could be upstream in gonadal, pituitary, or even hypothalamic cells, because these cells express VDR and respond to vitamin D (12, 25, 26, 27).

In any case, and whereas further investigations are necessary to ascertain this proposal, the present findings provide support for the hypothesis that VDR genotype may influence intrauterine and early postnatal growth, directly or via interactions with gender-related growth regulators.

	Acknowledgments

 
The authors wish to thank all the biologists at the Centre des Bilans de Santé de l’Enfant and Drs. S. Ferrari, J. P. Bonjour, J. A. Eisman, J. C. Carel, and P. Bougnères for their very helpful and friendly interest and advice.

	Footnotes

 
¹ Part of this work has been supported by Grant AOB-94013 from the Délégation à la Recherche Clinique, Assistance Publique des Hôpitaux de Paris.

Received February 25, 1997.

Revised May 6, 1997.

Accepted June 5, 1997.

	References

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